ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology

ARTICLE IN PRESS
Clinical Nutrition (2006) 25, 245–259
http://intl.elsevierhealth.com/journals/clnu
ESPEN GUIDELINES
ESPEN Guidelines on Enteral Nutrition:
Non-surgical oncology$
J. Arendsa,, G. Bodokyb, F. Bozzettic, K. Fearond, M. Muscaritolie,
G. Selgaf, M.A.E. van Bokhorst-de van der Schuereng, M. von Meyenfeldth,
DGEM:$$ G. Zürcher, R. Fietkau, E. Aulbert, B. Frick, M. Holm,
M. Kneba, H.J. Mestrom, A. Zander
a
Department of Medical Oncology, Tumor Biology Center, Albert-Ludwigs-Universität, Freiburg, Germany
Department of Oncology, Szent László Kórház, Budapest, Hungary
c
Department of Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy
d
Clinical and Surgical Sciences (Surgery), Royal Infirmary, The University of Edinburgh, Edinburgh, UK
e
Department of Clinical Medicine Clinica, Università di Roma ‘‘La Sapienza’’, Roma, Italy
f
Latvian Oncological Centre, Riga, Latvia
g
Department of Nutrition and Dietetics, VU medisch centrum, Amsterdam, The Netherlands
h
Department of Surgery, Academisch Ziekenhuis, Maastricht, The Netherlands
b
Received 20 January 2006; accepted 20 January 2006
KEYWORDS
Guideline;
Clinical practice;
Evidence-based;
Enteral nutrition;
Tube feeding;
Oral nutritional
supplements;
Oncology;
Summary Enteral nutrition (EN) by means of oral nutritional supplements (ONS)
and tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake
in cases where normal food intake is inadequate.
These guidelines are intended to give evidence-based recommendations for the
use of ONS and TF in cancer patients. They were developed by an interdisciplinary
expert group in accordance with officially accepted standards, are based on all
relevant publications since 1985 and were discussed and accepted in a consensus
conference.
Undernutrition and cachexia occur frequently in cancer patients and are
indicators of poor prognosis. EN should be started if undernutrition already exists
Abbreviations: TF, tube feeding; ONS, oral nutritional supplements; EN, enteral nutrition. This is used as a general term to include
both ONS and tube feeding. When either of these modalities is being discussed separately this is specified in the text; Normal food/
normal nutrition, normal diet as offered by the catering system of a hospital including special diets; PEG, percutaneous endoscopic
gastrostomy; RCT, randomised controlled trial
$
For further information on methodology see Schütz et al.144 For further information on definition of terms see Lochs et al.145 For
cancer patients receiving surgery see guidelines ‘‘Surgery incl. Organ Transplantation’’ Weimann et al.146
Corresponding author. Tel.: +49 761 2061890; fax: +49 761 2061892.
E-mail address: [email protected] (J. Arends).
$$
The authors of the DGEM (German Society for Nutritional Medicine) guidelines on enteral nutrition in oncology are acknowledged
for their contribution to this article.
0261-5614/$ - see front matter & 2006 European Society for Clinical Nutrition and Metabolism. All rights reserved.
doi:10.1016/j.clnu.2006.01.020
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246
J. Arends et al.
Radiotherapy;
Hematopoietic stem
cell transplantation;
Chemotherapy;
Malnutrition;
Undernutrition;
Cachexia;
Wasting
or if food intake is markedly reduced for more than 7–10 days. Standard formulae are
recommended for EN. Nutritional needs generally are comparable to non-cancer
subjects. In cachectic patients metabolic modulators such as progestins, steroids and
possibly eicosapentaenoic acid may help to improve nutritional status. EN is
indicated preoperatively for 5–7 days in cancer patients undergoing major
abdominal surgery. During radiotherapy of head/neck and gastrointestinal regions
dietary counselling and ONS prevent weight loss and interruption of radiotherapy.
Routine EN is not indicated during (high-dose) chemotherapy.
The full version of this article is available at www.espen.org.
& 2006 European Society for Clinical Nutrition and Metabolism. All rights reserved.
Summary of statements: Non-surgical oncology
Subject
Recommendations
Grade144
Number
General
Nutritional assessment of cancer patients should be
performed frequently, and nutritional intervention
initiated early when deficits are detected.
There are no reliable data that show any effect of enteral
nutrition on tumour growth. Such theoretical
considerations should, therefore, have no influence on the
decision to feed a cancer patient.
C
1.1
C
4.1
Start nutritional therapy if undernutrition already exists or
if it is anticipated that the patient will be unable to eat for
47 days.
Start enteral nutrition if an inadequate food intake (o60%
of estimated energy expenditure for 410 days) is
anticipated. It should substitute the difference between
actual intake and calculated requirements.
In weight losing patients due to insufficient nutritional
intake enteral nutrition should be provided to improve or
maintain nutritional status.
C
2.2
C
2.2
B
2.3
Perioperative
Patients with severe nutritional risk benefit from
nutritional support 10–14 d prior to major surgery even if
surgery has to be delayed.
A
3.1
During radio- or
radiochemotherapy
Use intensive dietary advice and oral nutritional
supplements to increase dietary intake and to prevent
therapy-associated weight loss and interruption of
radiation therapy.
Routine enteral nutrition is not indicated during radiation
therapy.
A
3.2
C
3.2
During
chemotherapy
Routine enteral nutrition during chemotherapy has no
effect on tumour response to chemotherapy or on
chemotherapy-associated unwanted effects and,
therefore, is not considered useful.
C
3.3
During stem cell
transplantation
The routine use of enteral nutrition is not recommended.
C
3.4
If oral intake is decreased parenteral nutrition may be
preferred to tube feeding in certain situations (i.e.
increased risk of haemorrhage and infections associated
with enteral tube placement in immuno-compromised and
thrombocytopenic patients).
C
3.4
Indication
General
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ESPEN Guidelines on Enteral Nutrition
In incurable
patients
247
Provide enteral nutrition in order to minimise weight loss
as long as the patient consents and the dying phase has not
started.
C
3.6
When the end of life is very close most patients only
require minimal amounts of food and little water to reduce
thirst and hunger.
B
3.6
Small amounts of fluid may also help to avoid states of
confusion induced by dehydratation.
Subcutaneously infused fluids in hospital or at home may
be helpful and also provide a vehicle for the administration
of drugs.
B
3.6
C
3.6
Application
Prefer the enteral route whenever feasible.
Administer preoperative enteral nutrition preferably
before admission to the hospital.
A
C
3.1
3.1
Route
Use tube feeding if an obstructing head or neck or
esophageal cancer interferes with swallowing or if severe
local mucositis is expected.
C
3.2
During radio- or
radiochemotherapy
Tube feeding can either be delivered via transnasal or
percutaneous routes.
3.2
Because of the radiation induced oral and esophageal
mucositis a percutaneous gastrostomy (PEG) may be
preferred.
C
3.2
Use standard formulae.
C
1.5
Regarding o-3 fatty acids, randomised clinical trial
evidence is contradictory/controversial and at present it is
not possible to reach any firm conclusion with regard to
improved nutritional status/physical function.
It is unlikely that o-3 fatty acids prolong survival in
advanced cancer.
C
2.5
Perioperative
Use preoperative enteral nutrition preferably with immune
modulating substrates (arginine, o-3 fatty acids,
nucleotides) for 5–7 d in all patients undergoing major
abdominal surgery independent of their nutritional status.
A
3.1
During stem cell
transplantation
Enteral administration of glutamine or eicosapentanoic
acid is not recommended due to inconclusive data.
C
3.5
In the presence of systemic inflammation pharmacological
efforts are recommended in addition to nutritional
interventions to modulate the inflammatory response.
In cachectic patients steroids or progestins are
recommended in order to enhance appetite, modulate
metabolic derangements, and prevent impairment of
quality of life.
Administer steroids for short-term periods only weighing
their benefits against their adverse side-effects.
Consider the risk of thrombosis during progestin therapy.
C
2.3
A
2.4
C
2.4
C
2.4
Type of formula
General
Drug treatment
Grade: Grade of recommendation; Number: refers to statement number within the text.
2.5
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248
1. Tumour and nutritional status
1.1. What is cancer cachexia?
In the majority of tumour-bearing patients
systemic proinflammatory processes are activated. Resulting metabolic derangements include insulin resistance, increased lipolysis and
high normal or increased lipid oxidation with
loss of body fat, increased protein turnover with
loss of muscle mass and an increase in production of acute phase proteins.
The systemic inflammatory reaction that develops with many cancers is an important cause of
loss of appetite (anorexia) and weight. The
syndrome of decreased appetite, weight loss,
metabolic alterations and inflammatory state is
referred to as cachexia, cancer cachexia or
cancer anorexia–cachexia syndrome (CACS).
These cytokine-induced metabolic alterations
appear to prevent cachectic patients from
regaining body cell mass (BCM) during nutritional support, are associated with a reduced
life expectancy (III), and are not relieved by
exogenous nutrients alone. Attempts to modulate these changes by other means should be
integrated into the management of cancer
patients (C). Nutritional assessment of cancer
patients should be performed frequently, and
nutritional intervention initiated early when
deficits are detected (C).
Comment: While undernutrition, both moderate
and severe, is frequent in patients with malignant
disease, many tumour-bearing patients display
elevated inflammatory markers.1–4 The observed
release of cytokines, catabolic hormones and
further regulatory peptides appears to be the
primary reaction of the cancer patient’s host
tissues.1–3 In addition, substances produced by
tumour cells, such as tumour lipid mobilising factor
(LMF) and proteolysis inducing factor (PIF), may
add catabolic signals and further stimulate cytokine
production and the acute phase response.5,6 The
systemic inflammatory reaction is assumed to be
involved in causing loss of appetite7 and body
weight8–11 and may facilitate tumour progression.12,13 Cytokine-induced metabolic alterations
also appear to prevent cachectic patients from
regaining BCM during nutritional support14 and are
associated with a reduced life expectancy.4,6,8,15–17
Impaired glucose tolerance due to insulin resistance was an early finding in cancer patients.18 The
relation of insulin to catabolic hormones is altered
and an increased cortisol secretion as well as a
J. Arends et al.
reduced insulin:cortisol ratio are common.2,19 As a
result glucose turnover and gluconeogenesis are
increased.3
Weight loss in cancer patients is accompanied by
a loss of fat as well as by enhanced plasma levels of
triglycerides. Lipid oxidation can be normal or
increased. What causes the alterations in lipid
metabolism remains unclear.2 However, increased
lipolysis is frequently observed.20,21 Simultaneously, lipid oxidation is increased21–23 or in the
high normal range,24 while glucose oxidation is
impaired. These observations may be taken to
support recommendations to increase the fat/
carbohydrate ratio in feeding cancer patients.
The pro-inflammatory milieu5,25 induces skeletal
muscle proteolysis3,26 resulting in a loss of muscle
mass and simultaneously leads to an increased
production of acute phase proteins. The ATP- and
ubiquitin-dependent proteasome proteolytic system
is activated at an early stage.27,28 Thus, cachexia
should be no longer considered a late stage phenomenon. Rather, since the metabolic and molecular
mechanisms ultimately leading to the phenotypic
pattern of the anorexia–cachexia syndrome are
already operating early during tumour growth and
development, cachexia should be seen as a partially
preventable phenomenon, the onset of which could
be at least delayed by means of early pharmacolo29
gical and nutritional intervention.
1.2. Does cancer influence nutritional status?
Yes. Weight loss is frequently the first symptom
occurring in cancer patients. Depending on
tumour entity, weight loss is reported in 30 to
more than 80% of patients and is severe (410%
of initial weight) in some 15% (IIb).
Comment: Weight loss preceding tumour diagnosis
has been reported by many groups to occur in
31–87% of the patients, depending on the tumour
entity30–33 (III). A severe involuntary weight loss of
more than 10% of initial weight over the previous 6
months has already occurred in 15% of all patients
at the time of diagnosis.30 Eighty-five per cent of
patients with pancreatic or stomach cancer have
lost weight at the time of diagnosis, and in 30% the
loss was severe.30 Both frequency and severity of
weight loss are correlated with tumour stage34 (III).
Quite often, when toxicity of treatment outweighs
tumour response, cancer therapies are associated
with anorexia and further weight loss35,36 (IV).
1.3. Does nutritional status influence the clinical
course and the prognosis?
An impaired nutritional status is associated with
reduced quality of life, lower activity level,
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ESPEN Guidelines on Enteral Nutrition
increased treatment-related adverse reactions,
reduced tumour response to treatment and
reduced survival (IIb). However, a cause–effect
relationship has not yet been established.
Comment: Longitudinal studies have demonstrated
that the prognosis for cancer patients with weight
loss is worse than that for weight-stable patients.
There are more pronounced treatment-related
adverse reactions,33 the response to cancer treatment is impaired,30,33,37 and there is reduced
activity level,30,33 subjective quality of life33,38
and survival30,33,37–43 (IIb; III). Next to sepsis,
cachexia is one of the commonest causes of death
in cancer, ranging from 5% to 25%44–47 (III).
In a recent trial total body nitrogen was found to
be the most powerful predictor of neutropenia after
chemotherapy in breast cancer patients48 (III).
Undernutrition, therefore, appears to be a
marker of disease severity and poor prognosis,
although it has not been established, whether
undernutrition per se has a direct influence on
prognosis, independently of the underlying disease.
1.4. Does cancer influence energy expenditure?
Cancer itself does not have a consistent effect
on resting energy expenditure. Oncological
treatment, however, may modulate energy expenditure (III).
Comment: Resting energy expenditure (REE) can
be unchanged, increased or decreased in relation
to the predicted energy expenditure. The energy
requirements of cancer patients should therefore
be assumed to be normal unless there are specific
data showing otherwise. In about 25% of patients
with active cancer, REE measured by the gold
standard method, indirect calorimetry, is more
than 10% higher, and in another 25% it is more than
10% lower than predicted energy expenditure. The
extent or direction of the error cannot be predicted
for individual cases49,50 (III). The mean value in a
group of cancer patients did not differ from the
mean value of healthy subjects50,51 (III). Studies in
subjects with different types of tumour reported
normal REE in patients with gastric or colorectal
cancers52,53 (III) and higher than expected REE in
subjects with pancreatic or lung cancers53–55 (III).
The increase in REE in lung cancer patients is
related to the presence of a systemic inflammatory
response56 (III) More detailed investigations in
patients with advanced small cell lung or pancreatic cancer demonstrated a relative increase in REE,
while physical activity level and total energy
expenditure (TEE) were decreased when compared
to predicted values for healthy individuals54,55 (III).
249
Thus, if REE cannot be measured in individual cases
then assumption of TEE calculated from equations
is acceptable.
As a rule-of-thumb the following assumptions for
TEE can be made for non-obese patients using the
actual body weight:
Ambulant patients : 30235 kcal=kgBW=d;
Bedridden patients : 20225 kcal=kgBW=d:
These assumptions are less accurate for severely
underweight (actual TEE per kg is higher in this
group) and for severely overweight subjects (actual
TEE per kg is lower). More accurate estimates of
REE may be obtained from published reference
calculations derived from healthy subjects57–59 (III).
There are few and inconsistent data regarding
effects of cancer treatments on energy expenditure. Hansel et al. studied 15 patients with colorectal cancer and did not observe any effects of
curative surgery or of hepatic metastases on REE52
(III). Fredrix et al. compared REE in healthy
controls and 104 patients with gastric or colorectal
cancer and 40 patients with non-small cell lung
cancer before and 1 year after surgery. Subjects
with gastrointestinal cancer had normal REE, which
rose slightly after surgery, while lung cancer
patients had elevated REE which fell after curative
resection, although not if there was tumour
recurrence53 (III). Chemotherapy treatment in
twelve patients with newly diagnosed small cell
lung cancer reduced both circulating inflammatory
mediators and REE60 (III).
1.5. Do cancer patients require a distinct
nutrient composition?
Standard formulae are recommended for enteral
nutrition (EN) of cancer patients (C).
Comment: There are no data from controlled
studies to suggest a cancer-specific enteral formula. Since glucose tolerance may be impaired18
(III) while lipid oxidation is normal or increased,21–24 lipids might be the preferred substrate for cancer patients. However, only a few
studies have compared lipid-free and lipid-containing nutrition and have found no clear difference in
effectiveness61: in these studies the parenteral and
not the enteral route of feeding was used. Therefore, standard formulae can be safely and effectively employed (IV).
The optimal nitrogen supply for cancer patients
cannot be determined at present.61 Recommendations range between a minimum protein supply of
1 g/kgBW/d62 and a target supply of 1.2–2 g/kgBW/
d61 (IV). The special case of metabolic modulation
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250
by o-3 fatty acids is considered in statement 2.5 of
this chapter.
There are no data—other than in perioperative
nutrition—available on the effects of formulae
enriched with glutamine or other immune modulating substances on the nutritional status of cancer
patients.
If patients experience a feeling of early satiety
and refuse the full volume of the prescribed EN,
then high-energy and high-protein formulae may be
preferable (IV).
Nutrition must be supplemented with electrolytes, trace elements and vitamins.63 For EN,
recommendations are based on the RDA/AI levels.64
Because markers of oxidative stress are elevated
and levels of antioxidants are decreased in cancer
patients65 [III], inclusion of increased doses of
antioxidant vitamins might be suggested; however,
there are no data to demonstrate a clinical benefit
from this.
2. Indications and goals of EN
2.1. What are specific nutritional goals in cancer
patients?
Therapeutic goal for cancer patients is the
improvement of function and outcome by:
preventing and treating undernutrition,
enhancing anti-tumour treatment effects,
reducing adverse effects of anti-tumour
therapies,
improving quality of life.
Comment: An improvement in survival due to
nutritional interventions has not yet been demonstrated convincingly. However, it should be considered that the main reason for the lack of
evidence of benefit in terms of survival is that all
randomised controlled trials (RCTs) have included,
for ethical reasons, only those cancer patients with
undisturbed oral intake, normal body weight, and
without significant weight loss. Cancer patients
who are unable to swallow will starve but may
survive several months with tube feeding (TF).
In a small randomised trial (n ¼ 60) oral supplementation with fish oil resulted in a significant
prolongation of survival in patients with advanced
cancers66 (Ib). However, the trial population was
small and heterogeneous and no other RCT has yet
shown a similar survival advantage.
A recent study in colorectal cancer patients
undergoing radiotherapy indicates that nutritional
counselling improves patient outcomes (nutritional
J. Arends et al.
status, Subjective Global Assessment and European
Organisation for Research and Treatment of Cancer
(EORTC) Quality of Life Questionnaire). Nutritional
counselling was shown to be as effective as high
energy and high protein ONS during radiotherapy,
whereas after three months of radiotherapy ‘‘it was
the only method to sustain a significant impact on
patient outcomes’’.67
EN may allow completion of radiation therapy
without interruption68,69 and perioperative EN may
reduce complications of major abdominal cancer
surgery (see also statement 3.2).
2.2. When should EN be started?
Nutritional therapy should be started if undernutrition already exists or if it is anticipated
that the patient will be unable to eat for more
than seven days. EN should also be started if an
inadequate food intake (o60% of estimated
energy expenditure) is anticipated for more
than 10 days (C).
It should substitute the difference between
actual intake and calculated requirements (C).
Comment: Despite inconsistent data the consensus
group has agreed upon the above recommendations. Several groups and nutritional societies have
published guidelines concerning when to initiate EN
in patients with decreased oral intake.70–75 These
recommendations are generally based on clinical
experience or expert committee reports.
If nutritional intake is chronically reduced, then
a corresponding weight loss and a concomitant
worsening of prognosis are anticipated (see also
statement ‘‘Does cancer influence nutritional status?’’). To demonstrate a reduced intake of normal
food, a simple 24 h recall is usually adequate. If this
proves difficult in individual cases, it may be
appropriate to ask the patient whether his/her
nutritional intake is less than 50% (low intake) or
less than 25% (minimal intake) of their usual intake
before the onset of the disease.
2.3. Can EN maintain or improve nutritional
status in cancer patients?
Yes. In patients who are losing weight due to
insufficient nutritional intake, EN should be
provided to improve or maintain nutritional
status (B). This may also contribute to the
maintenance of quality of life (Ib).
In the presence of systemic inflammation, however, it appears to be extremely difficult to
achieve whole body protein anabolism in cancer
patients. In these situations in addition to nutritional interventions pharmacological efforts
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ESPEN Guidelines on Enteral Nutrition
are recommended to modulate the inflammatory
response (C).
Comment: In a recent systematic review Baldwin
and Parsons evaluated 24 randomised trials comparing nutritional counselling alone, ONS alone, or
nutritional counselling plus ONS in people with
illness-related undernutrition. In this review ten
studies involving cancer patients were included76
(Ib). There were no significant differences in mortality or morbidity between the treatment groups.
However, those receiving ONS gained significantly
more or lost significantly less weight than those who
received nutritional counselling alone. Unfortunately,
only two studies involving cancer patients were
evaluable for this comparison76 (Ib).
Nutritional intervention can prevent or at least
ameliorate any deterioration in nutritional status
when normal eating is still possible but inadequate
to meet nutritional needs. Bozzetti evaluated
studies on the role of EN in cancer cachexia and
found a stabilising effect of this treatment in
situations where a deterioration of nutritional
status was anticipated77 (III). Lindh et al. were
able to halt weight loss by administering
30–40 kcal/kgBW/d by TF to patients with advanced gastrointestinal cancer who were losing
weight78 (III). Ongoing weight loss could also be
stopped in 93 patients with oropharyngeal and
oesophageal cancer using EN given via a PEG79 (III).
Similar results were found in 20 patients with lung,
breast or ovarian cancer using ONS80 (III) and in 200
patients with unresected pancreatic cancer using
ONS enriched with fish oil in half of the patients81
(IIa). Other studies also observed reductions in
weight loss with EN in patients with head and neck
or oesophageal cancers82–84 [III].
Recently, Isenring et al. demonstrated, in comparison to standard care, smaller reductions in
weight and quality of life when intensive nutritional counselling and ONS were offered to oncology outpatients receiving radiotherapy to the
gastrointestinal or head and neck areas85 (Ib).
Ravasco et al. randomised 111 colorectal cancer
outpatients, referred for radiotherapy, to nutritional counselling, high protein ONS or neither of
these. While they observed no difference in weight
changes between the three groups, nutritional
counselling or ONS resulted in significantly better
energy intake, protein intake and improvement in
quality of life function scores67 (Ib).
In the presence of systemic inflammation it
appears to be extremely difficult to regain lost
body cell mass by supplying energy and substrates
alone.2,8,10,14,86,87 Since, without effective antitumour therapy, it is impossible to reverse this
251
process, the Ethics Committee of Baylor College in
Houston (‘‘if no physiological benefit anticipated’’)
decided to declare the use of PEG unethical in
patients with malignant anorexia–cachexia syndrome and to reject it.88 This extreme view was
questioned in a detailed German comment, since
there is evidence to show that maintaining weight
or minimising weight loss through nutritional intervention can result in the maintenance of mobility
and quality of life.89 Furthermore, it should be
considered that total macronutrient deprivation in
ill subjects is associated with substantial mortality
within a few weeks. Hence cancer patients who are
unable to eat and who are going to die early from
pure starvation rather than from tumour progression, can benefit from nutritional support.
2.4. Can metabolic modulators increase nutritional intake?
Steroids or progestins are recommended in order
to enhance appetite (prevention of weight loss),
modulate metabolic derangements, and prevent
impairment of quality of life in cachectic
patients (A).
Steroids should preferably be administered for
short-term periods only and their benefits
weighed against their adverse side-effects (C).
The risk of thrombosis during progestin therapy
has to be considered (C).
Comment: RCTs90,91 (Ib) have demonstrated that
steroids can improve appetite, nausea, pain intensity
and/or parameters of subjective quality of life (five
studies) and that progestins improved appetite,
nutritional intake, body weight and mood (nine
studies). Stabilisation or improvement in body fat
mass can be achieved, whereas no impact on fat free
or muscle mass has been reported.92–95 One RCT
observed no effect of progestin (38 cancer patients,
480 mg megestrol acetate for 12 weeks)93 (Ib). Two
systematic reviews of randomised studies on the
effect of progestins in cancer anorexia or cachexia
found a significant benefit of progestins on appetite,
on weight gain and on quality of life96,97 (Ia). A
decrease in cytokine levels may be involved in the
anti-anorectic mechanism of progestins98,99 (III).
Androgens may induce an increase in body
weight, but they are less efficient than steroids or
progestins in stimulating appetite and oral intake;
however, unwanted effects during androgen therapy are less frequent than during treatment with
steroids and are comparable to those of progestins100 (Ib).
o-3 fatty acids are competitive antagonists of
the o-6 eicosanoid precursor arachidonic acid and
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252
are converted to less active pro-inflammatory
mediators.101 o-3 fatty acids have been studied in
cancer patients to improve appetite and body
weight (see 2.5).
2.5. Does supplementation with x-3 fatty acids
have a beneficial effect in cancer patients?
Randomised clinical trial (RCT) evidence is
contradictory/controversial and at present it is
not possible to reach any firm conclusion with
regard to improved nutritional status/physical
function (C). It is unlikely that x-3 fatty acids
prolong survival in advanced cancer.
Comment: Eicosapentaenoic acid (EPA) can be
administered in capsules as mixed marine triglycerides (fish oil) or as a semi-purified ethyl ester.
EPA has also been administered (as fish oil) in
combination with a high protein, high energy ONS
or in combination with other anti-cachectic agents
such as megestrol acetate.
There are only two placebo controlled, randomised trials of sufficient duration (44 weeks) to
assess weight, function or survival as end-points.
Gogos et al. (n ¼ 60) did not address effects of EPA
on nutritional status but showed a significant
prolongation of survival66 (Ib). However, the trial
population was small and heterogeneous and no
other RCT has shown a survival advantage for an
EPA-containing arm.
The Scotia Trial (ESPEN 2005, n ¼ 518) has
demonstrated a non-significant but potentially
clinically relevant treatment effect on weight
(P ¼ 0:06) and physical function (P ¼ 0:04) with a
dose of 2 g but not 4 g EPA diethyl ester (Ib).
Compliance with the capsule regimen has not yet
been reported but may have been different in the
two treatment arms.
In a randomised but uncontrolled small trial
Takatsuka et al. reported on 16 consecutive
patients, 7 of whom received 1.8 g/d EPA orally
from 30 days before until some 180 days after
allogeneic HSCT102 (IIa). EPA lowered levels of
prostanoids and cytokines and complications of
HSCT were less and the survival rate was significantly higher in the group treated with EPA.
There are two other RCTs (44 weeks duration)
where EPA (as fish oil) in combination with an ONS
has been tested against an alternative regimen. In
the trial reported by Fearon et al. (n ¼ 200) EPA/
ONS was compared with the ONS alone81 (Ib). On an
intention to treat analysis there was no advantage
from addition of EPA to the ONS. However,
compliance was suboptimal (only 70% of intended
dose) and measurement of plasma EPA levels
revealed that a substantial proportion of the
J. Arends et al.
patients in the ONS arm had been taking fish oil
capsules. In the trial reported by Jatoi et al.
(n ¼ 410) EPA/ONS was compared with megestrol
acetate alone or megestrol acetate plus EPA/
ONS103 (Ib). The authors concluded that EPA/ONS
either alone or in combination with megestrol
acetate did not improve weight or appetite more
than megestrol acetate alone. This study is difficult
to interpret as the primary end-point was weight
gain of more than 10%. Body composition was not
measured and it is therefore difficult to exclude the
possibility that fluid retention (a known side-effect
of megestrol acetate) confounded the trial result.
Moreover, compliance was not measured.
Further evidence is contradictory. In a short-term
(two weeks duration) placebo-controlled trial
Bruera et al. studied 60 weight losing cancer
patients and found no effect of 1.8 g EPA/day on
appetite, tiredness, nausea, well-being, caloric
intake, nutritional status or function104 (Ib). Ingested EPA will accumulate in tissues over time and
two weeks may be too short to induce clinically
measurable effects.105
Recent findings obtained in an uncontrolled
phase II study suggest that o-3 fatty acids may
induce weight stabilisation or weight gain in a small
subset of patients with cancer-related cachexia,
when administered in doses of 4.7 g EPA/day, that
were more than twice those used in the previously
published phase III trials105 (IIb). Similarly, in a very
small randomised study Persson et al. supplied 4.9 g
of EPA and 3.2 g of docosahexaenoic acid to
cachectic cancer patients and observed more
frequent weight stabilisation compared to the
control group106 (Ib).
The efficacy of treatment with EPA/ONS appears
to be critically dependent on the patients’ compliance. In addition to anorexia, patients’ compliance with prescribed high-energy and high-protein
EPA/ONS is limited by the frequently complained
unpleasant aftertaste. Therefore, it will be necessary to improve the palatability of EPA/ONS in order
to improve patients’ compliance with treatment
and hopefully its effectiveness.
The results of further trials are awaited.
3. EN in special situations
3.1. What is the indication for perioperative EN
in cancer patients?
General indications for perioperative EN also apply
for cancer patients. The strongest recommendations relevant to cancer patients refer to
severe nutritional risk states and to preoperative
ARTICLE IN PRESS
ESPEN Guidelines on Enteral Nutrition
nutrition. Refer to guidelines ‘‘Surgery incl.
Organ Transplantation’’ for further details and
comments.
Patients with severe nutritional risk benefit
from nutritional support for 10–14 days prior
to major surgery even if surgery has to be
delayed (A). Whenever feasible, the enteral
route should be preferred (A).
In all cancer patients undergoing major abdominal surgery preoperative EN preferably with
immune modulating substrates (arginine, x-3
fatty acids and nucleotides) is recommended
for 5–7 days independent of their nutritional
status (A).
3.2. Is there an indication for EN during radiotherapy or combined radio-chemotherapy?
Yes. Use intensive dietary counselling and ONS to
increase dietary intake (A) and to prevent
therapy-associated weight loss and interruption
of radiation therapy in patients undergoing
radiotherapy of gastrointestinal or head and
neck areas (A). If an obstructing head and neck
or oesophageal cancer interferes with swallowing, EN should be delivered by tube (C). TF is also
suggested if severe local mucositis is expected,
which might interfere with swallowing, e.g. in
intensive radiotherapy or in combined modality
radio-chemotherapy regimens including radiation
of throat or esophagus (C).
TF can either be delivered via the transnasal or
percutaneous routes. Because of radiation induced oral and esophageal mucositis a PEG may
be preferred (C).
Routine EN is not indicated during radiation
therapy of other body regions (C).
Comment: It is generally accepted that the
concomitant mucositis during radio/chemotherapy
results in weight loss in head and neck or
esophageal cancer patients68,84,107 (IIb): this loss
cannot be completely prevented by nutritional
counselling.108 In a small randomised pilot study
in 17 patients mouth swishes with a glutamine
solution reduced objective signs but not subjective
symptoms of radiation-induced mucositis; there
was no effect on body weight109 (IIa). However, a
randomised study performed in 60 oncology outpatients receiving radiotherapy to the gastrointestinal (12%) or head and neck areas (78%)
documented statistically smaller deteriorations in
weight, nutritional status and global quality of life
253
when intensive, individualised nutritional counselling and ONS were used instead of standard
nutritional care which included general advice
and a nutrition booklet85 (Ib). A recent metaanalysis of three randomised controlled studies
concluded, that in patients undergoing radiotherapy ONS significantly increase energy intake by
381 kcal/d110 (Ia).
A prospective trial in 50 head and neck cancer
patients treated with definitive ambulatory radiation therapy showed that ONS increased total
protein and total energy intake but could not
reduce weight loss69 (IIa). Nayel et al. studied 32
head and neck cancer patients during radiation
therapy of whom eleven were randomised to
receive ONS. All patients in the study group gained
weight and underwent radiation therapy without
interruption, whereas 7 of the 12 remaining
patients lost weight and in 5 the radiation therapy
had to be interrupted111 (Ib). Bozzetti et al.83 have
demonstrated that home EN is able to prevent a
deterioration in nutritional status among dysphagic
undernourished patients with esophageal cancer
receiving CT and RT, while non-dysphagic patients
who did not receive EN actually lost weight.
In one prospective83 and several retrospective82,84,112,113 (III) trials ONS or TF were shown to
significantly reduce weight loss compared to
normal food. As a consequence, quality of life
could be maintained107 (IIb), interruptions of
treatment could be prevented68 (IIb),91 (III) and
the frequency of hospital admissions could be
reduced68,83 (IIb),82 (III).
There are no RCTs comparing PEG with nasogastric TF in this setting. Radiotherapy of throat and/
or hypopharynx, however, regularly results in a
dose-dependent mucositis, which is still present 4
weeks after completion of radiotherapy.114 In one
retrospective study the authors reported that their
patients preferred PEG over nasogastric TF.115 Lees
compared prospectively the outcome of 100 head
and neck cancer patients with either PEG or
nasogastric TF. Both methods were found to be
equally effective at maintaining body weight, but
PEG was found to be superior since it was
associated with greater mobility, better cosmetic
appearance and improved subjective quality of
life.116 Roberge evaluated the impact of three
weeks of home EN via nasogastric TF in 39
consecutive patients treated for head and neck or
oesophageal cancer, and reported that some 60% of
the patients experienced psychological problems
and 25% experienced social strain117 (III).
There are no clinical studies reporting relevant
data on the administration of glutamine or other
substrates in radiotherapy patients.
ARTICLE IN PRESS
254
3.3. Is there an indication for routine EN during
chemotherapy?
No. Routine EN during chemotherapy has no
effect on tumour response to chemotherapy nor
on chemotherapy-associated unwanted effects.
Therefore, based on the available knowledge it
is considered not useful (B).
Comment: In 1994 Klein and Koretz analysed seven
RCTs investigating EN in combination with chemotherapy118 (Ib). Evaluation proved difficult since
all the studies differed in important details, the
patient groups were heterogeneous and underwent
different anti-cancer therapies, different nutritional formulae were administered, the studies
differed in length and timing of the nutritional
regimens and the sample sizes were small. Importantly, the studies were carried out mainly in
patients with normal or only moderately impaired
nutritional status. No obvious advantage of EN
could be observed with regard to survival, response
to treatment or toxicity of chemotherapy.
A recent meta-analysis of four RCTs concluded,
that in patients undergoing chemotherapy/radiotherapy ONS or TF had no effect on mortality when
compared to routine care.110 It has to be assumed,
however, that if response to anti-tumour treatment is
lacking, stabilisation of weight cannot be anticipated,
since additive catabolic effects result from both the
inflammatory response and the chemotherapy.
3.4. Is there an indication for routine EN during
autologous or allogeneic hematopoietic stem cell
transplantations (HSCT)?
No. There are no proven effects on tumour
response, therapy-associated side effects, graft
survival, graft-versus-host disease or overall
survival. The routine use of EN, therefore, is
not recommended (C). In addition, if oral intake
is decreased, the increased risk of haemorrhage
and infections associated with enteral tube
placement in immuno-compromised and thrombocytopenic patients has to be considered; in
certain situations, therefore (e.g. allogeneic
HSCT) parenteral nutrition (PN) may be preferred to TF (C).
Comment: After autologous transplantations nutritional intake is restricted for only a short time,
whereas after allogeneic transplantations more
intensive and long-term problems occur. Autologous patients are generally not in need of nutritional support. Patients undergoing allogeneic
transplantation receive PN early after intervention
in most transplantation centres since EN is usually
not well tolerated.119–121
J. Arends et al.
There are very few studies investigating EN
during HSCT. Two small trials in adult patients did
not distinguish between autologous and allogeneic
transplantation.122,123 Szeluga et al. conducted a
prospective RCT comparing an individualised EN
program (counselling, high protein snacks and/or
TF) in 57 patients (Ib). EN was more cost effective
but otherwise there were no differences in outcome between the two regimens.122 Roberts et al.
reported retrospectively on their experiences with
16 patients, who received EN via PEG123 (III). Similarly, in pediatric patients undergoing bone marrow
transplantation, a comparative study showed, that
TF is possible and equal in efficacy to PN, but only
rarely patients could be fed exclusively by EN.124
3.5. Is enteral delivery of glutamine or EPA useful
in hematopoietic stem cell transplantation?
Current study findings are inconclusive and
therefore the expert group reached a consensus
not to recommend the enteral administration of
glutamine or EPA in patients undergoing haematopoietic stem cell transplantation (C).
Comment: None of the four trials investigating oral
glutamine could prove any major advantages125–128
(Ib). Anderson et al. studied 193 patients and
observed that 4 g/day oral glutamine decreased the
severity and duration of oropharyngeal mucositis in
autologous but not in allogeneic transplantation
patients.125 Neither Schloerb and Skikne126 (n ¼ 66
patients) nor Coghlin Dickson et al.127 (Ib) (n ¼ 58
patients) found positive effects of 30 g/d of
glutamine in patients after allogeneic or autologous
transplantation. In addition, in a small RCT in 24
patients after autologous HSCT oral glutamine
(16 g/d) had no effect on the incidence of oral
mucositis, the frequency of diarrhoea nor on the
recovery of haemoglobin, white blood cells or
platelets.128 Thus, consensus exists that further
well designed clinical studies are needed to
definitely assess the benefits of supplementation
of GLN as a single oral supplement or as part of an
enteral formula on outcome of HSCT patients.129
Takatsuka et al. reported on 16 consecutive
patients, 7 of whom received 1.8 g/d EPA orally
from 30 days before until some 180 days after
allogeneic HSCT102 [IIa]. Complications of HSCT
were less and the survival rate was significantly
higher in the group treated with EPA.
3.6. Is there an indication for EN in advanced
stages of incurable cancer patients?
EN should be provided in order to minimise
weight loss, as long as the patient consents and
ARTICLE IN PRESS
ESPEN Guidelines on Enteral Nutrition
the dying phase has not started (C). When the
end of life is very close, most patients require
only minimal amounts of food and little water to
reduce thirst and hunger (B). Small amounts of
fluid may also help to avoid states of confusion
induced by dehydration (B). Subcutaneously
infused fluids in hospital or at home may be
helpful and also provide a vehicle for the
administration of drugs (C).
See also chapter ‘‘Ethical and legal aspects of
enteral nutrition’’.
Comment: Patients with incurable disease may
have, despite the lack of further available anticancer therapies, a life expectancy of several weeks
or months. If the expected survival due to spread of
the cancer exceeds 2–3 months, which is the
survival time of a completely starving subject, it
can be reasonably expected that EN will prolong
the survival of an incurable cancer patient, who is
unable to eat130 (IV).
Close to the end of life, guidelines for preserving
nutritional state are no longer relevant and
intensive nutritional therapy may worsen the
condition of dying cancer patients131 (IV). McCann
et al. treated 32 terminally ill mentally aware
patients for a median of 40 days and documented
the amount of food and fluids necessary to relieve
hunger and thirst; 20 patients experienced no
hunger and either no thirst or thirst only initially;
in all patients, symptoms of hunger and thirst could
be alleviated with small amounts of foods and
fluids132 (III). In a palliative care unit Bruera et al.
demonstrated that most terminal cancer patients
could be adequately treated by subcutaneous
hydration at a daily volume of some 1000 ml133
(III). Subcutaneous infusions can be administered at
home safely and effectively.134 The symptom of dry
mouth is very frequent but does not correlate with
the state of hydration or the amount of fluid
given;135 however, it may be alleviated by the use
of ice chips and lubrication to the lips132 (III).
Since it may be difficult to judge the expected
survival time of a cancer patient and thus the
potential benefit of EN, these patients should be
seen and discussed together by the oncologist, the
nutritionist and the palliative care specialist, and
the treatment designed on a personalised basis.
4. Risks of EN
4.1. Does EN ‘‘feed’’ the tumour?
There are no reliable data that show any effect
of EN on tumour growth. Such theoretical
255
considerations should, therefore, have no influence on the decision to feed a cancer patient (C).
Comment: There are no well-controlled clinical
studies by which this issue may be judged. There
are, however, a number of observations in cancer
patients treated with parenteral nutrition (PN) or
EN. All of these studies where performed in
patients with gastrointestinal or head and neck
cancers.
Comparing tumour and normal tissues, Cao et al.
showed an increase in S+G2+M-phases in gastric
cancer tissue but not in normal mucosa during PN,
while at the same time a positive nitrogen balance
was reached136 (III). Two other groups, however,
taking biopsies from head and neck137 (III) or
gastrointestinal cancer patients138 (III) could not
demonstrate any effect of PN on tumour cell
kinetics.
McNurlan et al. reported increased rates of
protein synthesis in both muscle and tumour tissue
removed at surgery after preceding intravenous
nutrition infusions139 (III). Comparing preoperative
PN in patients with colorectal cancer and noncancerous diseases, Ota et al. observed an increase
in red blood cell putrescine levels in cancer
patients but not in the other group140 (III).
Baron et al.141 (III) and Bozzetti et al.142 (III)
compared total PN to normal food in undernourished patients with head and neck or gastric
cancers, respectively. Both groups reported an
increase in tumour cell proliferation by PN.
Recently, Bozzetti et al. by using positron emission
scanning demonstrated that, in the fasting state,
glucose uptake by liver metastases from colorectal
cancer is remarkably elevated compared to normal
liver, but that there is no additional effect of
glucose- or lipid-based parenteral nutrition143 (III).
Finally, only one group compared the effects of
EN versus normal food on cell cycle distribution in
head and neck cancer patients (Edstrom et al.,
1989) and reported a larger increase in cell
proliferation after EN.
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